Insulin has important effects as a metabolic regulator via its ability to lower blood glucose. However, insulin is also a strong mitogenic (growth) factor. Therefore, the majority of monogenic insulin resistance syndromes are associated with short stature. Our research group has identified a patient with an extremely rare insulin resistance syndrome associated with overgrowth and tall stature. This syndrome, insulin-mediated pseudoacromegaly (IMPA), is characterized by extremely high levels of insulin, tall stature, acromegalic features, obesity, and hirsutism. Exome sequencing revealed that this proband carries 2 rare, potentially deleterious variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and beta-Klotho (KLB), both of which are in the Fibroblast Growth Factor 21 (FGF21) signaling pathway. KLB is a transmembrane co-factor that is required for FGF21 to bind to and activate FGFR1, resulting in activation of intrinsic tyrosine kinase activity and subsequent signal transduction. FGF21 is a predominantly liver-derived circulating hormone. FGF21 is an important part of the metabolic response to starvation. It promotes insulin sensitivity in muscle and adipose tissue by permitting glucose uptake and fatty acid oxidation. FGF21 also contributes to growth hormone resistance via downregulation of hepatic STAT5 and IGF-1 and upregulation of IGF-1 binding protein 1. Therefore, resistance to FGF21 could explain this patient?s severe insulin resistance and tall stature. Increased levels of FGF21 is associated with obesity, fatty liver, atherogenic lipid profiles, and reduced bone mineral density. Pharmacologic administration of FGF21 imparts resistance to high fat diet-induced weight gain, improves glucose tolerance and hepatic and peripheral insulin sensitivity (without triggering hypoglycemia), and normalizes hyperinsulinemia and hypertriglyceridemia. Interestingly, resistance to FGF21 is similar to high circulating insulin and leptin concentrations in insulin- and leptin-resistant states, respectively. We posit that, together, these variants in FGFR1 and KLB are pathogenic, leading to a FGF21 resistant state. This could explain this proband?s severe insulin resistance, tall stature, and hirsutism. In this R21 proposal we will: 1) Determine whether IMPA associated FGFR1 and KLB variants together impair FGF21 signaling; and 2) Characterize the physiology and metabolism of mice carrying IMPA mutations in Fgfr1 and Klb. Together these aims serve as a functional genomic approach towards identifying the mechanism of a novel insulin resistance syndrome. Additionally, these studies will improve our understanding of FGF21 biology in humans. This has additional relevance for common disorders of insulin resistance such as type 2 diabetes and metabolic syndrome.